Abstract
Disrupted endothelial permeability plays a crucial role in the vasculitis pathogenesis of Kawasaki disease (KD), which leads to pathological vascular leak and facilitates inflammatory cell infiltration in vascular lesions; however, the mechanisms involved in the development of endothelial barrier dysfunction during KD vasculitis are still largely unclear. Here, we found that sera from patients with KD can induce endothelial cell (EC) hyperpermeability compared to sera from healthy controls. We observed that serum vascular endothelial growth factor (VEGF) levels were increased in KD patients and sera from KD patients upregulated the expression of VEGF receptor 2 (VEGFR2) and neuropilin-1 (NRP1) in human coronary artery endothelial cells (HCAECs). Intriguingly, compared with silence of VEGFR2 in HCAECs, NRP1 silence resulted in a marked decrease in EC permeability. Furthermore, soluble NRP1 (sNRP1) remarkably reduced the stimulation of EC permeability by sera from KD patients compared with bevacizumab treatment. Importantly, we showed that besides VEGF, angiopoietin-like-4 (ANGPTL4), a NRP1-binding vasoactive factor, was also increased in KD and contributed to the EC permeability in KD conditions. In addition, levels of both ANGPTL4 and VEGF were inversely correlated with albumin levels in the serum of KD patients. Collectively, the data demonstrated that overexpressed NRP1, along with upregulated VEGFR2, in HCAECs treated with KD sera promotes endothelial permeability via interaction with the increased ANGPTL4 and VEGF in KD. Neutralization of hyperpermeability factors by sNRP1 may be a novel therapeutic strategy for KD vasculitis.
Highlights
Kawasaki disease (KD) is a common febrile pediatric disorder of unknown etiology and unclear pathogenesis with an increasing incidence and a leading cause of acquired heart disease in children under 5 years old [1]
Vascular endothelial growth factor (VEGF) is the most well-described pathological hyperpermeability mediator; by binding with its receptors on endothelial cell (EC), vascular endothelial growth factor (VEGF) exerts a powerful promotion of vascular permeability, which may contribute to the leakage of substances in plasma, such as albumin, and the subendothelium infiltration of blood cells in KD [5]
We found that the levels of ANGPTL4 were significantly increased in the KD group, whereas semaphorin3A levels had no significant change between KD and HC, which indicated that ANGPTL4 may participate in KD sera-stimulated EC hyperpermeability via interaction with NRP1
Summary
Kawasaki disease (KD) is a common febrile pediatric disorder of unknown etiology and unclear pathogenesis with an increasing incidence and a leading cause of acquired heart disease in children under 5 years old [1]. KD vasculitis is closely associated with increased vascular permeability that leads to vascular leakiness, decreased plasma proteins, and inflammatory cell infiltration of endothelium [3]. In the development of vascular leakage, vascular endothelial cell (EC) hyperpermeability induced by vasoactive factors has been shown to play a pivotal role [4]. Vascular endothelial growth factor (VEGF) is the most well-described pathological hyperpermeability mediator; by binding with its receptors on ECs, VEGF exerts a powerful promotion of vascular permeability, which may contribute to the leakage of substances in plasma, such as albumin, and the subendothelium infiltration of blood cells in KD [5].
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